Irritable Bowel Syndrome (IBS) is a motor disorder consisting of altered bowel habits, abdominal pain, and the absence of detectable pathology. IBS is recognized by its symptoms, which are markedly influenced by psychological factors and stressful life situations.
IBS is one of the most commonly encountered gastrointestinal disorders. Between 20% and 50% of patients referred to gastrointestinal clinics suffer from IBS. Symptoms of IBS occur in approximately 14% of otherwise apparently healthy people. It is one of the least understood disorders, in part because it is not a disease but a syndrome composed of a number of conditions with similar manifestations.
The major symptoms of IBS (altered bowel habits, abdominal pain and bloating) are manifestations of increased motility in the gut and hyper-secretion of gastric acid.
Activity of the GI tract is modulated neurally by the central nervous system (CNS) via parasympathetic and sympathetic innervation and by the peripherally located enteric nervous system (ENS) which resides within the GI tract itself.
The ENS is also very well organized and consists of all elements essential for coordinating the activity of the organ even in the absence of central input. See Goyal, R. K. "Neurology of the Gut", Gastrointestinal Disorders, Ed., Sleisenger and Fordtran, Saunders (1983), pp 97-114.
Serotonin (5-hydroxytryptamine, 5-HT) is associated directly or indirectly with a number of physiological phenomens, including appetite, anxiety and depression. R. A. Glennon J. Med. Chem. 30, 1 (1987). 5-HT receptors have been identified in the CNS and in peripheral tissues including the gastrointestinal tract, lung, heart, blood vessels, and various other smooth muscle tissues.
It has been recognized that there are multiple types of 5-HT receptors. These receptors have been classified as 5-HT1, 5-HT2, 5-HT3, and 5-HT4, with at least the 5-HT1 receptor being further divided into subclasses identified as 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT1D.
In the CNS, 5-HT receptors are located post-synaptically, on neurons that receive sertonergic input, and presynaptically on 5-HT releasing neurons. The presynaptic receptors are believed to function to sense the concentration of 5-HT in the synaltic cleft and modulate the further release of 5-HT accordingly.
Generally, an "agonist" is a chemical compound that mimics the action of the endogenous neurotransmitter at receptors.
Direct-acting serotonin agonists are chemical substances that bind to and mimic the action of serotonin on serotonin receptors.
Indirect-acting serotonin agonists are chemical substances that increase the concentration of serotonin in the synaptic cleft. Indirect serotonin agonists include inhibitors of a serotonin specific uptake carrier, agents that release serotonin from storage granules, agents (serotonin precursors) that increase serotonin formation, and monoamine oxidase (MAO) inhibitors that block serotonin degradation and thereby increase the amount of serotonin available.
Serotonin is known to have a number of actions in the gastrointestinal tract. It is known that the intravenous infusion in humans of 5-HT or 5-HTP (5-hydroxytryptophane) inhibits the volume and acidity of both spontaneous and histamine-induced gastric secretion while simultaneously increasing the production of mucus. Handbook of Experimental Pharmacology, Vol. XIX, "5-Hydroxytryptamine and Related Indolealkylamines", Erspamer, V., sub-ed., Springer-Verlog, N.Y., 1966, pp. 329-335. It is not known whether binding at one or some combination of 5-HT receptor sites is required to effect this inhibition response or which receptor(s) are involved.
It is known that 5-HT receptors in smooth muscle of the gastrointestinal tract mediate contraction of this tissue. The rat fundus and guinea pig ileum are widely used for in vitro studies of 5-HT agonists and antagonists. The enterochromaffin cells of the gastrointestinal tract are the major sites of 5-HT production in the body.
Motility in the gut is also greatly influenced by cholinergic receptors. It is known that acetylcholine enhances gastrointestinal motility by acting at muscarinic receptors. However, at least five different muscarinic receptors (M1-M5) are known. See Barry B. Wolfe: In the Muscarinic Receptors. Ed. By J. H. Brown, The Humana Press, N.J. 1989, pp 125-150.) The relative role of these receptors in modulating gastrointestinal motility is not known because selective agonists and antagonists of these receptors have not been identified. In IBS compounds acting as muscarinic antagonists, such as Bentyl, are useful therapies but show serious side effects.
Current treatment for IBS is restricted to drugs which treat only a small proportion of patients. For example, anticholinergic drugs reduce spasticity, thereby relieving some of the abdominal pain. On the other hand, histamine H.sub.2 receptor antagonists inhibit gastric acid secretion and, thus, may relieve dyspeptic symptoms. A therapeutic agent that relieves most of IBS symptoms is currently not available.
It has been discovered that 5HT1A agonists inhibit gastric acid secretion by acting directly on 5HT-receptor and, thus, may relieve dyspeptic symptoms. We have found a series of these agonist compounds that have also been shown to have affinity for M1-cholinergic receptors in binding studies and to have in vitro antispastic activity. Therefore, the compounds of this invention should be especially useful in the treatment of IBS.
This invention provides a group of compounds that are both direct acting 5-HT1A agonists and M1-cholinergic-receptor selective agents. Since these two characteristics are important to normalize the bowel habits and reduce the abdominal pain and distension of IBS, these agents which have this combination of activities should, therefore, act to normalize gastrointestinal motility and, be useful in the treatment of IBS conditions.
Other objects, features and advantages of the present invention will become apparent to one skilled in the art from the subsequent description and the appended claims.